It has been recognized that elevated levels of cholesterol in the blood plasma are a major risk factor of coronary heart disease in humans and that reducing plasma cholesterol level decreases the risk of coronary heart disease.
Cholesterol is a fat soluble steroid that is synthesized in the liver and is also introduced into the body through dietary intake. Cholesterol is present in the blood plasma, in part as the free steroid and in part as a lipid wherein the steroid is esterified with fatty acids, and is a raw material in the biosynthesis of cholesterol derivatives, e.g., bile acids. Bile acids are steroidal compounds, e.g., cholic acid, deoxycholic acid, that are synthesized from cholesterol in the liver and are recirculated, except for a small amount excreted in fecal matter, between the liver and the gastrointestinal tract as conjugates with the amino acids glycine and taurine. The bile acids aid in fat digestion in the intestine.
Plasma cholesterol level reflects a dynamic balance between factors tending to increase plasma cholesterol level, i.e., intake and biosynthesis of cholesterol, and factors tending to decrease plasma cholesterol level, i.e. the conversion of cholesterol to other compounds and excretion of cholesterol derivatives from the body.
Successful approaches to controlling plasma cholesterol level have included dietary modification e.g., minimizing the intake of cholesterol-laden foods and of foods having a high fat content, inhibition of cholesterol biosynthesis and encouraging an increase in the amount of bile acids eliminated from the body.
Particulate resins, e.g., cholestyramine, described in U.S. Pat. No. 3,383,281, and cholestipol, described in U.S. Pat. No. 3,383,281, that are capable of sequestering bile acids are known. Such resins, when orally administered to a mammalian host, form complexes with bile acid conjugates in the intestine and are effective in blocking resorbtion of bile acids from the intestine. The resin and sequestered bile acids are subsequently excreted from the body in fecal matter thereby increasing the rate at which bile acids are eliminated from the body. Other factors being equal, an increase in the rate at which bile acids are eliminated from the body tends to lower plasma cholesterol level by accelerating the conversion of cholesterol to bile acids in order to maintain a constant supply of bile acids. A portion of the cholesterol for this increased synthesis of bile acids is supplied by removal of cholesterol from the blood plasma.
The bile acid sequestrants are orally administered in various forms. Most typically, the sequestrant is taken as a mixture with a food item.
While the capacity of known sequestrants for bile acids is such that dosages effective in lowering serum cholesterol in humans typically fall in the range of about 10 to 15 grams/day, dosages of up to about 50 grams/day may be required. The particulate bile sequestrant resins can be unpleasant to ingest, particularly when large dosages are required. Adverse side reactions such as bloating, gas formation, constipation and diarrhea are common among patients to whom the resins are administered.
There has been a continuing effort in this field to minimize the unpleasant side effects associated with a therapeutically effective bile acid sequestrant regimen by developing sequestrants that have an increased ability to sequester bile acids relative to that of cholestyramine and cholestipol and which are effective in the reduction of serum cholesterol when administered at lower dosages than presently required using cholestyramine and cholestipol.